Molecular Control of Bone Formation
Description: PROJECT NARRATIVE The US population us advancing with age and healthy elderly adults maintain more active life styles, while fracture risk increases with age due to gradual bone degeneration. Current therapies that seek to reduce bone loss or improve bone mineral density can have major clinical side-effects or cause patient discomfort, and they cannot be used on all patients. Therefore, there is a significant need to find new methods for improving bone quality that are based on a thorough understanding of how bone forms. This project has identified a bone stimulatory drug that is already safely used in the clinic for other indications. This drug (GSK126) targets an enzyme (Enhancer of Zeste Homolog-2, EZH2) that controls the molecular memory (epigenetics) of osteoblasts by generating tiny molecular bookmarks (lysine methylation) on proteins that control packaging of DNA into either readable (‘open chromatin’) or unreadable (‘heterochromatin’) regions. At present, our mechanistic understanding of EZH2 is limited and does not yet permit consideration of clinical applications. However, our findings to date are encouraging and indicate that inhibition of EZH2 function is remarkably osteogenic and stimulates bone accrual, while blocking this protein does not affect other musculoskeletal lineages (e.g., cartilage and tendon). We are now using EZH2 inhibition as a tool to understand at what developmental stages it acts to regulate bone formation (Aim 1) and precisely through which molecular networks the enzyme achieves its biological effects (Aim 2). By modulating the activity of this enzyme through multiple loss of function approaches, we will be able to establish which main signaling pathways are controlled by EZH2 as a molecular blueprint for the conversion of immature mesenchymal cells to osteoblasts that support formation of bone. EZH2 is the first epigenetic regulator known to suppress osteoblastogenesis, and therefore its inhibition can activate bone formation through ‘double-negative’ stimulation. Hence, this proposal characterizes a ‘first-in- class’ druggable epigenetic enzyme and as such is expected to have a major impact on clinical strategies to control fracture risk and a range of short-term bone anabolic applications. Furthermore, these studies will address the fundamentally important biological question as to how humans grow and maintain bone tissue through novel epigenetic regulatory pathways.
Funding type: research
Funder scheme: R01
Start date: 2003-09-30
End date: 2023-08-31
Investigator: JENNIFER J WESTENDORF
Institution: MAYO CLINIC ROCHESTER
Funded outputs count: 339
Funder award ID: R01AR049069
OpenAlex ID: G2809131488